Tri-, tetra-substituted-3-aminopyrrolidine derivative

Abstract

A quinolone synthetic antibacterial agent and a therapeutic agent for an infection which exhibit broad spectrum and strong antibacterial activity for both Gram positive and Gram negative bacteria, and which are also highly safe are provided. The compound provided is represented by following formula (I): wherein R 1 and R 2 represent hydrogen atom, or the like; R 3 represents an alkyl group containing 1 to 6 carbon atoms, or the like; R 4 and R 5 independently represents hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, or the like, with the proviso that R 4 and R 5 do not simultaneously represent hydrogen atom; or the substituents R 4 and R 5 together represent (a) a 3- to 6-membered cyclic structure including the carbon atom shared by R 4 and R 5 to form a spirocyclic structure with the pyrrolidine ring; R 6 and R 7 independently represents hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, or the like; R 8 represents a halogen-substituted alkyl group containing 1 to 6 carbon atoms, or the like; X 1 represents hydrogen atom or a halogen atom; A represents nitrogen atom or a moiety represented by formula (II):

1. A compound represented by following formula (I): 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein
 R 1  represents hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, or a substituted carbonyl group derived from an amino acid, a dipeptide, or a tripeptide; the alkyl group being optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms; 
 R 2  represents hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, or a cycloalkyl group containing 3 to 6 carbon atoms; the alkyl group being optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms; 
 R 3  represents an alkyl group containing 1 to 6 carbon atoms,or a cycloalkyl group containing 3 to 6 carbon atoms;an alkenyl group containing 2 to 6 carbon atoms; or an alkynyl group containing 2 to 6 carbon atoms; the group being optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms; 
 R 4  and R 5  independently represent hydrogen atom, halogen atom, an alkenyl group containing 1 to 6 carbon atoms, an alknyl group containing 1 to 6 carbon atoms, or an alkenyl group containing 2 to 6 carbon atoms; an alkynyl group containing 2 to 6 carbon atoms, or an optionally substituted cycloalkyl group containing 3 to 6 carbon atoms; the alkyl group, the alkoxy group, the alkenyl group, and the alkynyl group being either a straight chain or branched group; the alkyl group being optionally substituted with a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms; and with the proviso that R 4  and R 5  are not simultaneously hydrogen atom; or 
 the substituents R 4  and R 5  together represent (a) a 3- to 6-membered cyclic structure including the carbon atom shared by R 4  and R 5  to form a spirocyclic structure with the pyrrolidine ring, the thus formed spiro ring optionally containing oxygen atom or sulfur atom as a ring member atom, and optionally being substituted with an alkyl group containing 1 to 6 carbon atoms optionally having a halogen atom or a substituent; or (b) exomethylene group bonding to the pyrrolidine ring by double bond, the exomethylene group optionally having 1 or 2 substituents selected from hydroxy group, amino group, halogen atom, an alkylthio group containing 1 to 6 carbon atoms, and an alkoxy group containing 1 to 6 carbon atoms; 
 R 6  and R 7  independently represent hydrogen atom or an alkyl group containing 1 to 6 carbon atoms; 
 R 8  represents a halogen-substituted alkyl group containing 1 to 6 carbon atoms, a halogen-substituted cycloalkyl group containing 3 to 6 carbon atoms, a halogen-substituted phenyl group, or a halogen-substituted heteroaryl group; 
 R 9  represents hydrogen atom, phenyl group, acetoxymethyl group, pivaloyl oxymethyl group, ethoxycarbonyl group, choline group, dimethyl aminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, an alkyl group containing 1 to 6 carbon atoms, an alkoxymethyl group containing 2 to 7 carbon atoms, or a phenylalkyl group comprising an alkylene group containing 1 to 6 carbon atoms and phenyl group; 
 X 1  represents hydrogen atom or a halogen atom; and 
 A represents nitrogen atom or a moiety represented by formula (II): 
 
       
         
           
           
               
               
           
         
       
       wherein X 2  represents hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, an alkoxy group containing 1 to 6 carbon atoms, cyano group, halogen atom, a halogen-substituted methyl group, or a halogenomethoxy group. 
     
     
       2. The compound, or a salt thereof according to  claim 1  wherein the compound represented by the formula (I) is a compound represented by the following formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X 1 , and A are as defined above. 
     
     
       3. The compound, or a salt thereof according to  claim 1  wherein R 1  and R 2  in the formula (I) are hydrogen atom. 
     
     
       4. The compound, or a salt thereof according to  claim 1  wherein either one of R 1  and R 2  in formula (I) is hydrogen atom and the other is a substituent selected from methyl group, ethyl group, fluoroethyl group, and cyclopropyl group. 
     
     
       5. The compound, or a salt thereof according to  claim 1  to wherein R 3  in formula (I) is methyl group or ethyl group. 
     
     
       6. The compound, or a salt thereof according to  claim 1  wherein either one of R 4  and R 5  in formula (I) is hydrogen atom and the other is fluorine atom, methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, or ethynyl group, cyclopropyl group, fluoromethyl group, methoxy group, vinyl group, or ethynyl group. 
     
     
       7. The compound, or a salt thereof according to  claim 1  wherein R 4  and R 5  in formula (I) together form cyclopropane ring or cyclobutane ring including the carbon atom shared by R 4  and R 5  to form a spirocyclic structure. 
     
     
       8. The compound, or a salt thereof according to  claim 1  wherein R 4  and R 5  in formula (I) together form an exoalkylene group. 
     
     
       9. The compound, or a salt thereof according to  claim 1  wherein X 1  in formula (I) is fluorine atom. 
     
     
       10. The compound, or a salt thereof according to  claim 1  wherein A in formula (I) is nitrogen atom. 
     
     
       11. The compound, or a salt thereof according to claims wherein A in formula (I) is a moiety represented by formula (II). 
     
     
       12. The compound, or a salt thereof according to  claim 1  wherein X 2  in formula (II) is methyl group, ethyl group, methoxy group, difluoromethoxy group, cyano group, or chlorine atom. 
     
     
       13. The compound, or a salt thereof according to  claim 1  wherein X 2  in formula (II) is methyl group or methoxy group. 
     
     
       14. The compound, or a salt thereof according to  claim 1  wherein R 8  in formula (I) is a 1,2-cis-2-halogenocyclopropyl group. 
     
     
       15. The compound, or a salt thereof according to  claim 1  wherein R 8  in formula (I) is a stereochemically pure 1,2-cis-2-halogenocyclopropyl group. 
     
     
       16. The compound, or a salt thereof according to  claim 15  wherein the 1,2-cis-2-halogenocyclopropyl group which is R 8  in formula (I) is (1R,2S)-2-halogenocyclopropyl group. 
     
     
       17. The compound, or a salt thereof according to  claim 15  wherein the (1R,2S)-2-halogenocyclopropyl group which is R 8  in formula (I) is (1R,2S)-2-fluorocyclopropyl group. 
     
     
       18. The compound, or a salt thereof according to  claim 1  wherein R 9  in formula (I) is hydrogen atom. 
     
     
       19. The compound, or a salt thereof according to  claim 1  wherein the compound of formula (I) is a stereochemically pure compound. 
     
     
       20. A compound selected from the group consisting of
 7-[3-amino-3,4-dimethylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[3-amino-3,4-dimethylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[3-amino-4-ethyl-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[3-amino-4-ethyl-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[3-amino-3-methyl-4-isopropyl pyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[3-amino-3-methyl-4-isopropyl pyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[3-amino-4-cyclopropyl-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[3-amino-4-cyclopropyl-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[3-amino-3-methyl-4-vinylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt 
 7-[3-amino-4-methylene-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[3-amino-4-methylene-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[3-amino-4-fluoromethyl-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[3-amino-4-fluoromethyl-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(3R)-3-amino-3-methyl-4-methylene pyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-(3-amino-4-methoxy-3-methylpyrrolidine-1-yl)-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-(3-amino-4-methoxy-3-methylpyrrolidine-1-yl)-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(3S,4S)-3-amino-4-fluoromethyl-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(3S,4S)-3-amino-4-fluoromethyl-3-methylpyrrolidine-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(3S,4S)-3-amino-4-fluoromethyl-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(3S,4S)-3-amino-4-fluoromethyl-3-methylpyrrolidine-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(3R)-3-amino-4-fluoro-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(3R)-3-amino-4-fluoro-3-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(3S)-3-amino-3-fluoromethyl-4-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(3S)-3-amino-3-fluoromethyl-4-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-6-fluoro-4-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[8-amino-8-methyl-6-azaspiro[3.4]octane-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; and 
 7-[(7S)-7-amino-7-methoxy-5-azaspiro[2.4]heptane-5-yl]-1-cyclopropyl-8-methyl -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof. 
 
     
     
       21. The compound, or a salt thereof according to  claim 18  wherein, in the compound of formula (I), absolute configuration at position 3 where amino group has substituted on the pyrroridine ring is (3R). 
     
     
       22. The compound, or a salt thereof according to  claim 18  wherein, in the compound of formula (I), absolute configuration at position 3 where amino group has substituted on the pyrroridine ring is (3S). 
     
     
       23. A compound selected from the group consisting of
 7-[7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[8-amino-8-methyl-6-azaspiro[3.4]octane-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[8-amino-8-methyl-6-azaspiro[3.4]octane-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; 
 7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptane-5-yl]-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof; and 
 7-[(3S)-3-amino-3-fluoromethyl-4-methylpyrrolidine-1-yl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, or a salt thereof. 
 
     
     
       24. The compound, or a salt thereof according to  claim 18  wherein, in the compound of formula (I), absolute configuration at the site where amino group has substituted on the spirobicyclic substituent is (R). 
     
     
       25. The compound, or a salt thereof according to  claim 18  wherein, in the compound of formula (I), absolute configuration at the site where amino group has substituted on the spirobicyclic substituent is (S). 
     
     
       26. pharmaceutical composition comprising a compound according to  claim 1 , a salt thereof, and a pharmaceutically acceptable carrier. 
     
     
       27. A method for treating a bacterial or microbial infection by administering the compound or a salt thereof of according to any one of  claims 1 ,  20 , and  23  to a subject in need thereof. 
     
     
       28. The compound, or a salt thereof according to  claim 19  wherein, in the compound of formula (I), absolute configuration at position 3 where amino group has substituted on the pyrroridine ring is (3R). 
     
     
       29. The compound, or a salt thereof according to  claim 19  wherein, in the compound of formula (I), absolute configuration at position 3 where amino group has substituted on the pyrroridine ring is (3S). 
     
     
       30. The compound, or a salt thereof according to  claim 20  wherein, in the compound of formula (I), absolute configuration at position 3 where amino group has substituted on the pyrroridine ring is (3R). 
     
     
       31. The compound, or a salt thereof according to  claim 20  wherein, in the compound of formula (I), absolute configuration at position 3 where amino group has substituted on the pyrroridine ring is (3S). 
     
     
       32. A pharmaceutical composition comprising a compound according to  claim 20 , a salt thereof, and a pharmaceutically acceptable carrier. 
     
     
       33. A pharmaceutical composition comprising a compound according to  claim 23 , a salt thereof, and a pharmaceutically acceptable carrier.